The overall objectives of this proposed research are to delineate pharmacokinetic parameters from the time course of absorption, distribution, metabolism and excretion of certain selected drugs that are implicated in abuse, using the dog as the basic animal model. These pharmacokinetic studies, after intravenous and oral administration of various doses, should show any dependence of obtained pharmacokinetic parameters on dose. Specific drugs to be studied will include morphine, codeine, heroin and selected narcotic antagonists, tetrahydrocannabinol and selected available metabolites such as the 11 hydroxy delta 9, 11 hydroxy delta 8 and the 8 hydroxy derivatives; and amobarbital. Analytical methodology will be continued to be developed so that these drugs and their available metabolites can be monitored in available biological fluids such as blood, urine and bile at the necessary levels to establish precise pharmacokinetic models. Our prior studies have produced methods applicable to the assay of such drugs and their metabolites at the picogram level, which is the necessary sensitivity to perform such studies. These developed analytical methods of high sensitivity are needed in forensic medicine. The protein binding and erythrocyte partition of these compounds will be determined. The physicochemical parameters and rate-pH profiles of these compounds, their interconversions and degradations will be evaluated. The specific example is for in vitro studies with the tetrahydrocannabinol where our preliminary evidence has demonstrated that the solvolytic degradations are rapid and highly pH dependent. Such studies are vital to understand and map in vivo transformations. The long term goals are to develop procedures and models to serve as the basis for the eventual evaluation of the pharmacokinetics of these compounds in human subjects, to correlate psychic and pharmacodynamic effects with the time courses of the drugs and their metabolites, and to define the mode of action of antagonists. BIBLIOGRAPHIC REFERENCES: Stability of Tetrahydrocannabinols I. E.R. Garrett and J. Tsau, J. Pharm. Sci. 63, 1563 (1974). Separation and Sensitive Analysis of Tetrahydrocannabinol, in Biological Fluids by HPLC and GLC. E.R. Garrett and C.A. Hunt, J. Pharm. Sci. 64 (in press) 1975.